PAPERS OF THE 134TH ASA ANNUAL MEETING
The Natural History of Main Duct–Involved, Mixed-Type Intraductal Papillary Mucinous Neoplasm Parameters Predictive of Progression Alexandra M. Roch, MD,∗ Eugene P. Ceppa, MD,∗ Mohammad A. Al-Haddad, MD,† John M. DeWitt, MD,† Michael G. House, MD,∗ Nicholas J. Zyromski, MD,∗ Attila Nakeeb, MD,∗ and C. Max Schmidt, MD, PhD, MBA, FACS∗
Objective: As such, the natural history of MPD-involved IPMN is poorly understood. Background: The high-risk of malignancy associated with main pancreatic duct (MPD)-involved intraductal papillary mucinous neoplasm (IPMN) has been established by surgical series. The International Consensus Guidelines recommend surgical resection of MPD-involved IPMN in fit patients. Methods: A review of a prospectively collected database (1992–2012) of patients with IPMN undergoing primary surveillance was performed. Invasive progression was defined as invasive carcinoma on pathology and/or positive cytopathology. Analyses included univariate, logistic regression, and receiver operating characteristic curve analyses. Results: A total of 503 patients with IPMN underwent primary surveillance, 70 for MPD-involved, mixed-type IPMN. Indications for intensive surveillance of these 70 high-risk patients were comorbidities, patient choice, and early/borderline MPD dilation (42%, 51%, and 7%, respectively). Mean follow-up was 4.7 years. Nine patients (13%) progressed at a mean of 3.5 (range, 1–9) years during follow-up. Univariate analyses yielded weight loss, interval (from isolated branch-duct IPMN) to MPD involvement, diffuse MPD dilation, increase of MPD diameter, absence of extra pancreatic cysts, elevated serum CA19-9 levels, and elevated serum alkaline phosphatase levels as significant. Maximum MPD and/or branch-duct diameter were not significant. In logistic regression, diffuse MPD dilation, serum CA19-9 and serum alkaline phosphatase levels, and absence of extra pancreatic cysts were predictors of invasiveness. The receiver operating characteristic curve indicated that the combination of these 4 factors achieved an accuracy of 98% in predicting progression. Conclusions: Primary surveillance of mixed-type IPMN may be a reasonable strategy in select patients. Diffuse MPD dilation, serum CA19-9, serum alkaline phosphatase, and absence of extrapancreatic cysts predict patients likely to progress during primary surveillance. Keywords: IPMN, mixed-type, natural history, predictors of invasive progression, surveillance (Ann Surg 2014;260:680–690)
From the ∗ Department of Surgery, Indiana University School of Medicine, Indianapolis; and †Department of Medicine, Division of Gastroenterology, Indiana University Hospital, Indianapolis. This article has been accepted for plenary session oral presentation at the 134th American Surgical Association Annual Meeting in Boston, MA, on April 12th, 2014. Disclosure: Dr C. Max Schmidt is consultant for Redpath IP, Inc and Asuragen, Inc. Reprints: C. Max Schmidt, MD, PhD, MBA, FACS, IU Health Pancreatic Cyst & Cancer Early Detection Center, 980 W Walnut St C522, Indianapolis, IN 46202. E-mail: [email protected]. C 2014 by Lippincott Williams & Wilkins Copyright ISSN: 0003-4932/14/26004-0680 DOI: 10.1097/SLA.0000000000000927
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hashi et al1 first described intraductal papillary mucinous neoplasm (IPMN) in 1982 in a series of 4 mucinous neoplasms of the pancreas with pancreatic ductal ectasia. After its description, physicians considered it a rare tumor that would only occur in a minority of patients and, owing to their potential malignant risk, surgical resection was recommended. With the improvement of imaging resolution and an increased awareness, IPMNs have become recognized as the most common of all cystic pancreatic tumors, accounting for up to 70% of them.2 In 1996, The World Health Organization first recognized IPMN as a distinct entity from mucinous cystic neoplasm and incorporated it into the International Histological Classification of tumors.3 All IPMNs are well-established pancreatic precancerous lesions, but on the basis of the location of ductal involvement (ie, branch or main duct), 3 IPMN subtypes with differential malignant risk have been described4 —branch-duct IPMN, main duct IPMN and the combination, mixed-type IPMN.5,6 The International Association of Pancreatology published recommendations (Sendai criteria) for management of IPMN in 2006,5 and an international, multidisciplinary group of experts updated them in 2012.6 The International Consensus Guidelines (ICGs) established indications for surveillance based on surgical series analyzing the rate and predictors of invasive progression according to IPMN subtype. The goal of IPMN surveillance is early detection of malignant transformation and intervention before development of invasive cancer. With an overall risk of malignant transformation ranging from 6% to 40%,7–9 close surveillance of branch-duct IPMN is considered reasonable in the absence of select high-risk criteria present at diagnosis or apparent during follow-up.5,6 This conservative management allows patients to avoid the morbidity and potential mortality associated with pancreatic resection.10,11 Although criteria suspicious for an invasive progression have been validated in branch-duct IPMN, no criterion (or a combination of criteria) has proved accurate in predicting an invasive progression in main pancreatic duct (MPD)–involved IPMN. Salvia et al,12 in a combined surgical series from Verona and Boston, found that patients with malignant main duct–involved IPMN were significantly older with more jaundice and/or worsening of diabetes. However, 29% of patients with malignant MPD-involved IPMN were asymptomatic. Similarly, Sugiyama et al13 concluded that symptoms, an MPD diameter of more than 15 mm and a mural nodule, were predictors of malignancy in main duct–involved IPMN but found that patients with smaller MPD diameter and no mural nodule had invasive carcinomas as well. On the basis of this limitation and on a malignant transformation risk ranging from 36% to 95%,9,10 the ICGs recommend resection of all main duct–involved IPMN (ie, main duct IPMN and mixed-type IPMN) in fit patients.5,6 As such, only case reports and small series have analyzed the surveillance of main duct– involved IPMN,14–17 resulting in very limited data available on its natural history. Annals of Surgery r Volume 260, Number 4, October 2014
Copyright © 2014 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Annals of Surgery r Volume 260, Number 4, October 2014
The objective of our study was to examine the outcomes of patients with main duct–involved IPMN, specifically, mixed type (mixed-type IPMN), not undergoing initial resection due to comorbidity, patient preference, or borderline MPD diameter criterion (range, 5–6 mm). We hypothesized that clinical, biologic, and radiographic parameters would predict pancreatic cancer risk in patients undergoing primary surveillance for main duct–involved IPMN.
METHODS Study Population All patients with a diagnosis of IPMN at Indiana University Hospital from 1992 to 2012 were included in this study. Only patients undergoing primary surveillance for main duct–involved, mixed-type IPMN were analyzed. Patients with isolated branch-duct IPMN or main duct IPMN were not included in our analysis. Data were collected and reported in strict compliance with patient confidentiality guidelines as defined by the Indiana University institutional review board.
Exclusion Criteria Patients without a diagnosis of mixed-type IPMN were not included in this study. Patients with less than 6 months of surveillance and 2 clinic visits (by a pancreatic surgeon or a pancreatologist) or patients with incomplete data also were excluded from this analysis.
Mixed-Type IPMN Diagnosis Mixed-type IPMN was defined, according to the 2012 ICGs, as the association of segmental or diffuse MPD dilation of 5 mm or greater (without any other cause of obstruction) and single/cluster or multiple pancreatic cysts of 5 mm or greater communicating with the MPD (branch ducts).6 Mixed-type IPMN was diagnosed on crosssectional [multidetector computed tomography (MDCT) or magnetic resonance imaging (MRI)/magnetic resonance cholangiopancreatography (MRCP)] and endoscopic [endoscopic ultrasonography (EUS), endoscopic retrograde cholangiopancreatography (ERCP) or pancreatic ductoscopy] imaging. Only patients with cytopathologically confirmed IPMN were evaluated. Cytopathologic diagnosis was based on fine-needle aspiration (FNA) of pancreatic fluid collected during EUS and, in select cases, via ductal lavage on ERCP or directed biopsies via pancreatic ductoscopy. Ductoscopy when performed also allowed visualization of the MPD epithelium, which aided in a positive diagnosis of mucinous epithelium in the MPD. Pancreatic directed endoscopy was performed by gastroenterologists with expertise in pancreatic disease and was often repeated in cases of nondiagnostic or inconclusive samples. MPD fluid and “cyst” fluids (typically sampled from the largest branch duct or multiple branch ducts in the case of multifocality) were aspirated via transduodenal FNA. A rapid preliminary result was provided the same day, and a final cytopathologic diagnosis based on a paraffinized cell pellet was made 2 to 3 days later by a cytopathologist with expertise in pancreatic disease. Cytology features considered diagnostic of IPMN included mucin-producing epithelial cells arranged in a papillary pattern in a background of thick viscous mucin.18–20
Follow-up IU Health Pancreatic Cyst and Cancer Early Detection Clinic performs surveillance based on “low” and “high” risk stratification groups. Patients with mixed-type IPMN would fall under a “high-risk” category. The surveillance protocol established for high-risk patients included a clinic visit (history and physical), with serum markers C 2014 Lippincott Williams & Wilkins
Surveillance of Mixed-Type IPMN
(amylase, lipase, alkaline phosphatase, hemoglobin A1c , and carbohydrate antigen (CA 19-9) and cross-sectional imaging (MRI/MRCP or MDCT) every 6 months. EUS-FNA and cytopathologic, biochemical (cyst carcinoembryonic antigen), and molecular (DNA quantity and quality, Kras mutation, loss of heterozygosity, and GNAS mutation) analyses were also recommended every 1 to 2 years in this high-risk population. In our mixed-type IPMN study group, patient compliance with this protocol was variable due to patient preference, travel constraints, and insurance considerations. In light of this, the actual surveillance protocol that was followed was closer to a clinic visit with serum markers and imaging every 6 to 12 months, and EUS-FNA every 2 to 3 years.
Assessment of Invasive Progression The assessment of an invasive progression21 in our patients was based on EUS-FNA of main and/or branch ducts with targeted biopsy of any mural nodule or solid component. Radiologically guided biopsy of secondary lesions (liver metastases, peritoneal carcinomatosis) was also performed if present. From EUS-FNA, invasive progression was affirmed in cases of positive cytopathology.22 Secondary lesion biopsy confirmed an invasive progression when it showed cells consistent with a metastasis from adenocarcinoma of pancreatic origin.
Parameters Assessed The sociodemographic parameters were assessed using a questionnaire and confirmed by the surgeon/gastroenterologist at the time of the clinic visit, along with the clinical and biological data. The overall sociodemographic and clinical characteristics were compared in mixed-type IPMN patients with or without an invasive progression (sex/age as a continuous variable/obesity/body mass index/history of smoking/alcohol abuse, personal history of other cancer, family history of pancreatic cancer, presence of symptoms in general/abdominal or back pain/nausea or vomiting/weight loss/steatorrhea/diabetes/acute pancreatitis/jaundice). The blood tests (amylase, lipase, alkaline phosphatase, hemoglobin A1c , CA19-9), EUS results (mural nodule), and imaging study findings (MPD diameter, unifocal/diffuse MPD dilation, size of branch-duct IPMN, multifocal branch-duct lesions, lymph nodes, extrapancreatic cysts) were also recorded and compared. All the EUS and imaging results were reviewed by a pancreatic surgeon and/or a pancreatologist. Diffuse main duct dilation was defined as dilation of the MPD throughout the entire pancreas. The following dynamic parameters were calculated: increase of main duct dilation (in millimeter and percentage), increase in size of branch-duct IPMN (in millimeter and percentage), time to main duct involvement (if initially isolated branch duct), speed of branchduct IPMN size increase, and speed of main duct diameter increase. The speed of increase was defined as the differential between the size/diameter at diagnosis and the maximal size/diameter, divided by the time to reach maximal size/diameter.
Statistical Analysis Data were compiled using Microsoft Excel 2011 (Microsoft Corp, Redmond, WA). Descriptive statistics of continuous data included mean, standard error, and range, whereas categorical variables were presented as percentages. Subgroup comparisons on continuous and categorical data were performed with the Student t test and the Fisher exact test, respectively. Statistical significance was considered at a P value of less than 0.05. Independent predictors of malignant progression were determined with univariate and multivariate analyses using a logistic www.annalsofsurgery.com | 681
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Annals of Surgery r Volume 260, Number 4, October 2014
Roch et al
regression model. Parameters associated with a P value of less than 0.1 on univariate analysis were candidate for the multivariate model. Only variables that remained statistically significant with a P value of less than 0.05 were included in the final model. To assess the performance characteristics of our model of predictors, we generated receiver operating characteristic curves and calculated the area under the curve. All analyses were performed using IBM SPSS statistics version 21.0 (IBM Corp, Armonk, NY).
RESULTS Population Characteristics Eight hundred sixty-five patients had a diagnosis of IPMN and were treated at Indiana University Medical Center from 1992 to 2012. Among them, 362 (41.8%) underwent primary surgical resection whereas 503 (58.2%) underwent primary surveillance. Of the 503 patients in the surveillance program, 95 (11%) were identified with MPD-involved IPMN (main duct IPMN and mixed-type IPMN). After exclusion of patients with incomplete data for analysis and patients with less than 6-month follow-up and 2 clinic visits, there remained 72 patients with MPD-involved IPMN. Of these, 70 patients (8.1%) had the mixed-type IPMN subtype and were included in this study. Those 70 patients were consisted of 40 men and 30 women (sex ratio = 1.33), with a mean age at initial diagnosis of 68.8 ± 11.2 (range, 33–85) years. Patient selection is summarized in Figure 1.
Primary Surveillance Indications for Nonsurgical Management Surgery was contraindicated in 29 of 70 patients (41.5%) because of 1 or multiple relevant and major comorbidities (American Association of Anesthesiologists score ≥3). Comorbidities included synchronous extrapancreatic malignancies in 4 patients (5.7%), cardiovascular disease in 13 patients (18.6%), respiratory insufficiency
in 5 patients (7.1%), end-stage renal insufficiency in 3 patients (4.3%), cirrhosis in 1 patient (1.4%), and various other comorbidities in the remaining 3 patients (4.3%) (eg, morbid obesity, chronic diseases requiring prolonged use of steroids). Thirty-six patients (51.4%) refused surgery after being appropriately informed of the invasive potential of their disease and the indication for surgical management. Finally, the 5 remaining patients (7.1%) underwent surveillance because of borderline criteria for mixed-type IPMN (MPD dilation; range, 5–6 mm). Of those 5 patients, 3 ultimately underwent surgical resection of their lesion during follow-up. Final pathology of the surgical specimen confirmed mixed-type IPMN in all 3 patients. For the remaining 2 patients, a diagnosis of mixed-type variant was made on cytopathology (aspiration of the MPD fluid had features diagnostic of IPMN on cytology).
Type and Duration of Surveillance Patients with a diagnosis of mixed-type IPMN on study underwent primary surveillance for a median of 4.5 years (mean = 4.7 ± 2.7 years; range, 0.6–10.2 years). Fifty-five patients (78.6%) underwent only surveillance, whereas 15 patients (21.4%) underwent primary surveillance and delayed surgery at a median of 2.4 years (mean 2.7 ± 2.1 years; range, 0.6–9 years) from the onset of primary surveillance. The indication for secondary surgery in 3 patients (4.3%) was a cytopathologic diagnosis of an invasive IPMN. The remaining 12 patients (80%) with secondary operations had noninvasive mixed-type IPMN (9 low-grade dysplasia and 3 moderate-grade dysplasia). Their indications for secondary surgery were symptoms (n = 5) [including weight loss (n = 2), recurrent acute pancreatitis (n = 2), new-onset diabetes (n = 1)], radiologic features (n = 4), increased main duct dilation (n = 1), increased branch-duct size (n = 1), increased uptake on positron emission tomography– computed tomography (n = 2), patient change in preference (n = 2), and molecular changes (n = 1) (specifically, increased clonality of mutations).
Invasive Progression Characteristics of Patients Who Progressed Nine patients (12.9%) progressed to invasive carcinoma during follow-up. Clinical aspects of patients with an invasive progression are summarized in Table 1. According to this table, 1 patient (11.1%) with an invasive progression did not meet either the Sendai criteria5 (symptoms, MPD diameter ≥15 mm, mural nodule, cyst size >3 cm) or the high-risk stigmata of the 2012 ICGs6 (jaundice, solid component, MPD diameter ≥10 mm). Of the 9 patients, 6 (66.7%) did not undergo surgery. Of these 6, 3 patients had stage IV disease involving liver (n = 2) or peritoneum (n = 1). Three patients had locally advanced tumor, specifically encasement of the celiac axis (n = 1), superior mesenteric artery (n = 1), or common hepatic artery (n = 1). Among the remaining 3 patients (33.3%) who underwent surgery, 2 received a diagnosis of locally advanced tumors intraoperatively. These patients did not undergo resection and underwent exploratory laparotomy (n = 1) and palliative double bypass (n = 1). Only 1 patient had pancreatic resection (pancreaticoduodenectomy). Pathology of the surgical specimen revealed T3N1M0 poorly differentiated adenocarcinoma (4.7 cm, with 9/18 positive lymph nodes).
Time to Progression FIGURE 1. Patients’ selection process. BD indicates branch duct; MT, mixed-type. 682 | www.annalsofsurgery.com
Progression of the 9 patients in this study to invasive mixedtype IPMN occurred at a median of 2.7 years (mean = 3.5 ± 2.6 years; range, 1–9 years). Annual cumulative risk of invasive carcinoma in our population of followed mixed-type IPMN is shown in Figure 2. C 2014 Lippincott Williams & Wilkins
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Annals of Surgery r Volume 260, Number 4, October 2014
Surveillance of Mixed-Type IPMN
TABLE 1. Characteristics of the 9 Patients with Invasive Progression of Mixed-Type IPMN Age, yr 62 80 64 67 73 77 58 52 85
Sex
Symptoms
Acute Pancreatitis
Jaundice
Maximal MPD Diameter, mm
Maximal BD Size, mm
Mural Nodule
Male Female Male Male Female Male Female Male Female
Yes Yes Yes No Yes No Yes Yes Yes
No No Yes No Yes No Yes No No
No No No No Yes Yes Yes No Yes
10 6 10 5 20 7 8 11 8
120 42 19 25 56 32 10 45 5
No No No No Yes No No Yes No
BD indicates branch duct.
FIGURE 2. Cumulative rate of patients who progressed and who did not progress according to the duration of surveillance after diagnosis of mixed-type IPMN.
There was a stepwise increase in the cumulative incidence of progression with duration of surveillance, resulting in 3- and 5-year invasive progression risks of 7.1% and 10%, respectively.
Uni- and Multivariate Analyses of Patients With Invasive Progression Versus Those Without Univariate Analysis Univariate analysis yielded the following potential predictors for an invasive progression as significant (Table 2): weight loss (P = 0.08), time to main duct involvement (P = 0.07), diffuse main duct dilation (P = 0.01), increase of main duct diameter (P = 0.02), absence of intra-abdominal extrapancreatic cysts (hepatic, renal, ovarian, splendid) (P = 0.009), elevated serum CA19-9 levels (defined as >37 units/mL) (P = 0.009), and elevated serum alkaline phosphatase levels (defined as >125 ng/mL) (P = 0.03). Interestingly, usual predictors of invasiveness (mural nodule, maximum main duct diameter, maximal branch-duct size, main duct diameter >10 mm, and branch-duct size > 30 mm) were not significant on univariate analysis (P = 0.17, P = 0.48, P = 0.98, P = 0.22, and P = 0.47, respectively). Because of its well-established association with invasive potential, jaundice was excluded from univariate and multivariate analyses. Of note, 29 patients (41%) received a diagnosis of 1 or multiple branch-duct IPMNs first with a delayed diagnosis of main duct involvement, which was then confirmed on cytopathology of the C 2014 Lippincott Williams & Wilkins
MPD fluid. In those cases, however, we considered the time when the main duct component was diagnosed as the starting point for all follow-up, invasive progression, and survival durations to avoid any bias.
Multivariate Model In logistic regression, diffuse main duct dilation, elevated serum CA19-9 levels, elevated serum alkaline phosphatase levels, and absence of extrapancreatic cysts were predictors of an invasive progression with odds ratios of 7.4, 10, 6.9, and 12.3, respectively (Table 3).
Performance of Predictors The receiver operating characteristic curve indicated that the combination of these 4 predictors (diffuse main duct dilation, elevated serum CA19-9 levels, elevated serum alkaline phosphatase levels, and absence of extrapancreatic cysts) achieved a sensitivity of 77.8% and a specificity of 98.4% in predicting invasiveness. This resulted in an accuracy of 98% for invasive progression prediction. In the group of patients without progression (n = 61), 16 patients (26.2%) had no predictor, 35 (57.4%) had 1 predictor, 9 (14.7%) had 2 predictors, 1 (1.6%) had 3 predictors, and none had all 4 identified predictors. Conversely, in the invasive progression group, no patient had zero or 1 predictor, 3 (33.3%) had 2 predictors, www.annalsofsurgery.com | 683
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Annals of Surgery r Volume 260, Number 4, October 2014
Roch et al
TABLE 2. Univariate Analysis Characteristics Sociodemographic Age, mean ± SD, yr Obesity, n (%) BMI, mean ± SD, kg/m2 History of smoking, n (%) Alcohol abuse, n (%) Personal history of cancer, n (%) Family history of pancreatic cancer, n (%) Clinical, n (%) Symptoms (in general) Abdominal/back pain Nausea/vomiting Weight loss Steatorrhea Diabetes Acute pancreatitis Biological, n (%) Elevated serum CA19-9 Elevated HbA1c Abnormal amylase Abnormal lipase Elevated serum alkaline phosphatase Radiological/endoscopic Mural nodule, n (%) Maximal MPD diameter, mean ± SD, mm MPD diameter >10 mm, n (%) Maximal BD size, mean ± SD, mm BD size >30 mm, n (%) Diffuse dilation MPD, n (%) Multifocal BD-IPMN, n (%) Lymph nodes, n (%) Absence of extrapancreatic cysts, n (%) Dynamic parameters, mean ± SD Increase dilation of MPD diameter, mm Increase dilation of MPD diameter, % Increase size BD, mm Increase size BD, % Time to MPD involvement Speed of MPD diameter increase, mm/yr Speed of BD size increase, mm/yr
No Invasive Progression (n = 61)
Invasive Progression (n = 9)
P
68.9 ± 11.3 17 (27.9) 27.6 ± 5.0 35 (57.4) 16 (26.2) 14 (23.0) 7 (11.5)
68.7 ± 10.9 0 (0) 23.8 ± 2.6 4 (44.4) 2 (22.2) 4 (44.4) 0 (0)
0.96 0.11 0.16 0.5 1 0.22 0.58
48 (78.7) 40 (65.6) 11 (18) 20 (32.8) 13 (21.3) 19 (31.1) 23 (37.7)
7 (77.8) 7 (77.8) 2 (22.2) 6 (66.7) 2 (22.2) 3 (33.3) 3 (33.3)
1 0.71 0.67 0.08∗ 1 1 1
8 (13.1) 17 (27.9) 4 (10) 1 (7.1) 12 (19.7)
5 (55.6) 5 (55.6) 1 (7.7) 3 (8.6) 5 (55.6)
0.009∗ 0.13 1 1 0.03∗
4 (6.6) 8.4 ± 4.7 14 (23) 22.5 ± 14.8 24 (39.3) 13 (21.3) 45 (73.8) 13 (21.3) 24 (39.3)
2 (22.2) 9.5 ± 4.4 4 (44.4) 38.3 ± 33.9 5 (55.6) 6 (66.7) 5 (55.6) 2 (22.2) 8 (88.9)
0.17 0.48 0.22 0.98 0.47 0.01∗ 0.26 1 0.009∗
1.4 ± 2.3 21.6 ± 32.8 6.1 ± 8.4 39.7 ± 60.2 0.72 ± 1.3 1.2 ± 2.6 2.9 ± 4.8
3.1 ± 5 58.5 ± 100 21.6 ± 27.6 263.7 ± 415.2 2 ± 3.1 2.1 ± 3.3 7.9 ± 11.2
0.02∗ 0.02∗ 0.76 0.150 0.07∗ 0.31 0.34
Elevated serum CA19-9 defined by CA19-9 >37 units/mL; elevated HbA1c defined by HbA1c >5.9%; abnormal serum amylase defined by serum amylase level 125 units/L; abnormal serum lipase defined by serum lipase level 51 units/L; elevated serum alkaline phosphatase defined by alkaline phosphatase >125 ng/mL. ∗ P value considered statistically significant in univariate analysis ( 37 units/mL; elevated serum alkaline phosphatase defined by alkaline phosphatase >125 ng/mL. ∗ P value considered statistically significant in univariate analysis (
The Natural History of Main Duct–Involved, Mixed-Type Intraductal Papillary Mucinous Neoplasm Parameters Predictive of Progression Alexandra M. Roch, MD,∗ Eugene P. Ceppa, MD,∗ Mohammad A. Al-Haddad, MD,† John M. DeWitt, MD,† Michael G. House, MD,∗ Nicholas J. Zyromski, MD,∗ Attila Nakeeb, MD,∗ and C. Max Schmidt, MD, PhD, MBA, FACS∗
Objective: As such, the natural history of MPD-involved IPMN is poorly understood. Background: The high-risk of malignancy associated with main pancreatic duct (MPD)-involved intraductal papillary mucinous neoplasm (IPMN) has been established by surgical series. The International Consensus Guidelines recommend surgical resection of MPD-involved IPMN in fit patients. Methods: A review of a prospectively collected database (1992–2012) of patients with IPMN undergoing primary surveillance was performed. Invasive progression was defined as invasive carcinoma on pathology and/or positive cytopathology. Analyses included univariate, logistic regression, and receiver operating characteristic curve analyses. Results: A total of 503 patients with IPMN underwent primary surveillance, 70 for MPD-involved, mixed-type IPMN. Indications for intensive surveillance of these 70 high-risk patients were comorbidities, patient choice, and early/borderline MPD dilation (42%, 51%, and 7%, respectively). Mean follow-up was 4.7 years. Nine patients (13%) progressed at a mean of 3.5 (range, 1–9) years during follow-up. Univariate analyses yielded weight loss, interval (from isolated branch-duct IPMN) to MPD involvement, diffuse MPD dilation, increase of MPD diameter, absence of extra pancreatic cysts, elevated serum CA19-9 levels, and elevated serum alkaline phosphatase levels as significant. Maximum MPD and/or branch-duct diameter were not significant. In logistic regression, diffuse MPD dilation, serum CA19-9 and serum alkaline phosphatase levels, and absence of extra pancreatic cysts were predictors of invasiveness. The receiver operating characteristic curve indicated that the combination of these 4 factors achieved an accuracy of 98% in predicting progression. Conclusions: Primary surveillance of mixed-type IPMN may be a reasonable strategy in select patients. Diffuse MPD dilation, serum CA19-9, serum alkaline phosphatase, and absence of extrapancreatic cysts predict patients likely to progress during primary surveillance. Keywords: IPMN, mixed-type, natural history, predictors of invasive progression, surveillance (Ann Surg 2014;260:680–690)
From the ∗ Department of Surgery, Indiana University School of Medicine, Indianapolis; and †Department of Medicine, Division of Gastroenterology, Indiana University Hospital, Indianapolis. This article has been accepted for plenary session oral presentation at the 134th American Surgical Association Annual Meeting in Boston, MA, on April 12th, 2014. Disclosure: Dr C. Max Schmidt is consultant for Redpath IP, Inc and Asuragen, Inc. Reprints: C. Max Schmidt, MD, PhD, MBA, FACS, IU Health Pancreatic Cyst & Cancer Early Detection Center, 980 W Walnut St C522, Indianapolis, IN 46202. E-mail: [email protected]. C 2014 by Lippincott Williams & Wilkins Copyright ISSN: 0003-4932/14/26004-0680 DOI: 10.1097/SLA.0000000000000927
680 | www.annalsofsurgery.com
O
hashi et al1 first described intraductal papillary mucinous neoplasm (IPMN) in 1982 in a series of 4 mucinous neoplasms of the pancreas with pancreatic ductal ectasia. After its description, physicians considered it a rare tumor that would only occur in a minority of patients and, owing to their potential malignant risk, surgical resection was recommended. With the improvement of imaging resolution and an increased awareness, IPMNs have become recognized as the most common of all cystic pancreatic tumors, accounting for up to 70% of them.2 In 1996, The World Health Organization first recognized IPMN as a distinct entity from mucinous cystic neoplasm and incorporated it into the International Histological Classification of tumors.3 All IPMNs are well-established pancreatic precancerous lesions, but on the basis of the location of ductal involvement (ie, branch or main duct), 3 IPMN subtypes with differential malignant risk have been described4 —branch-duct IPMN, main duct IPMN and the combination, mixed-type IPMN.5,6 The International Association of Pancreatology published recommendations (Sendai criteria) for management of IPMN in 2006,5 and an international, multidisciplinary group of experts updated them in 2012.6 The International Consensus Guidelines (ICGs) established indications for surveillance based on surgical series analyzing the rate and predictors of invasive progression according to IPMN subtype. The goal of IPMN surveillance is early detection of malignant transformation and intervention before development of invasive cancer. With an overall risk of malignant transformation ranging from 6% to 40%,7–9 close surveillance of branch-duct IPMN is considered reasonable in the absence of select high-risk criteria present at diagnosis or apparent during follow-up.5,6 This conservative management allows patients to avoid the morbidity and potential mortality associated with pancreatic resection.10,11 Although criteria suspicious for an invasive progression have been validated in branch-duct IPMN, no criterion (or a combination of criteria) has proved accurate in predicting an invasive progression in main pancreatic duct (MPD)–involved IPMN. Salvia et al,12 in a combined surgical series from Verona and Boston, found that patients with malignant main duct–involved IPMN were significantly older with more jaundice and/or worsening of diabetes. However, 29% of patients with malignant MPD-involved IPMN were asymptomatic. Similarly, Sugiyama et al13 concluded that symptoms, an MPD diameter of more than 15 mm and a mural nodule, were predictors of malignancy in main duct–involved IPMN but found that patients with smaller MPD diameter and no mural nodule had invasive carcinomas as well. On the basis of this limitation and on a malignant transformation risk ranging from 36% to 95%,9,10 the ICGs recommend resection of all main duct–involved IPMN (ie, main duct IPMN and mixed-type IPMN) in fit patients.5,6 As such, only case reports and small series have analyzed the surveillance of main duct– involved IPMN,14–17 resulting in very limited data available on its natural history. Annals of Surgery r Volume 260, Number 4, October 2014
Copyright © 2014 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Annals of Surgery r Volume 260, Number 4, October 2014
The objective of our study was to examine the outcomes of patients with main duct–involved IPMN, specifically, mixed type (mixed-type IPMN), not undergoing initial resection due to comorbidity, patient preference, or borderline MPD diameter criterion (range, 5–6 mm). We hypothesized that clinical, biologic, and radiographic parameters would predict pancreatic cancer risk in patients undergoing primary surveillance for main duct–involved IPMN.
METHODS Study Population All patients with a diagnosis of IPMN at Indiana University Hospital from 1992 to 2012 were included in this study. Only patients undergoing primary surveillance for main duct–involved, mixed-type IPMN were analyzed. Patients with isolated branch-duct IPMN or main duct IPMN were not included in our analysis. Data were collected and reported in strict compliance with patient confidentiality guidelines as defined by the Indiana University institutional review board.
Exclusion Criteria Patients without a diagnosis of mixed-type IPMN were not included in this study. Patients with less than 6 months of surveillance and 2 clinic visits (by a pancreatic surgeon or a pancreatologist) or patients with incomplete data also were excluded from this analysis.
Mixed-Type IPMN Diagnosis Mixed-type IPMN was defined, according to the 2012 ICGs, as the association of segmental or diffuse MPD dilation of 5 mm or greater (without any other cause of obstruction) and single/cluster or multiple pancreatic cysts of 5 mm or greater communicating with the MPD (branch ducts).6 Mixed-type IPMN was diagnosed on crosssectional [multidetector computed tomography (MDCT) or magnetic resonance imaging (MRI)/magnetic resonance cholangiopancreatography (MRCP)] and endoscopic [endoscopic ultrasonography (EUS), endoscopic retrograde cholangiopancreatography (ERCP) or pancreatic ductoscopy] imaging. Only patients with cytopathologically confirmed IPMN were evaluated. Cytopathologic diagnosis was based on fine-needle aspiration (FNA) of pancreatic fluid collected during EUS and, in select cases, via ductal lavage on ERCP or directed biopsies via pancreatic ductoscopy. Ductoscopy when performed also allowed visualization of the MPD epithelium, which aided in a positive diagnosis of mucinous epithelium in the MPD. Pancreatic directed endoscopy was performed by gastroenterologists with expertise in pancreatic disease and was often repeated in cases of nondiagnostic or inconclusive samples. MPD fluid and “cyst” fluids (typically sampled from the largest branch duct or multiple branch ducts in the case of multifocality) were aspirated via transduodenal FNA. A rapid preliminary result was provided the same day, and a final cytopathologic diagnosis based on a paraffinized cell pellet was made 2 to 3 days later by a cytopathologist with expertise in pancreatic disease. Cytology features considered diagnostic of IPMN included mucin-producing epithelial cells arranged in a papillary pattern in a background of thick viscous mucin.18–20
Follow-up IU Health Pancreatic Cyst and Cancer Early Detection Clinic performs surveillance based on “low” and “high” risk stratification groups. Patients with mixed-type IPMN would fall under a “high-risk” category. The surveillance protocol established for high-risk patients included a clinic visit (history and physical), with serum markers C 2014 Lippincott Williams & Wilkins
Surveillance of Mixed-Type IPMN
(amylase, lipase, alkaline phosphatase, hemoglobin A1c , and carbohydrate antigen (CA 19-9) and cross-sectional imaging (MRI/MRCP or MDCT) every 6 months. EUS-FNA and cytopathologic, biochemical (cyst carcinoembryonic antigen), and molecular (DNA quantity and quality, Kras mutation, loss of heterozygosity, and GNAS mutation) analyses were also recommended every 1 to 2 years in this high-risk population. In our mixed-type IPMN study group, patient compliance with this protocol was variable due to patient preference, travel constraints, and insurance considerations. In light of this, the actual surveillance protocol that was followed was closer to a clinic visit with serum markers and imaging every 6 to 12 months, and EUS-FNA every 2 to 3 years.
Assessment of Invasive Progression The assessment of an invasive progression21 in our patients was based on EUS-FNA of main and/or branch ducts with targeted biopsy of any mural nodule or solid component. Radiologically guided biopsy of secondary lesions (liver metastases, peritoneal carcinomatosis) was also performed if present. From EUS-FNA, invasive progression was affirmed in cases of positive cytopathology.22 Secondary lesion biopsy confirmed an invasive progression when it showed cells consistent with a metastasis from adenocarcinoma of pancreatic origin.
Parameters Assessed The sociodemographic parameters were assessed using a questionnaire and confirmed by the surgeon/gastroenterologist at the time of the clinic visit, along with the clinical and biological data. The overall sociodemographic and clinical characteristics were compared in mixed-type IPMN patients with or without an invasive progression (sex/age as a continuous variable/obesity/body mass index/history of smoking/alcohol abuse, personal history of other cancer, family history of pancreatic cancer, presence of symptoms in general/abdominal or back pain/nausea or vomiting/weight loss/steatorrhea/diabetes/acute pancreatitis/jaundice). The blood tests (amylase, lipase, alkaline phosphatase, hemoglobin A1c , CA19-9), EUS results (mural nodule), and imaging study findings (MPD diameter, unifocal/diffuse MPD dilation, size of branch-duct IPMN, multifocal branch-duct lesions, lymph nodes, extrapancreatic cysts) were also recorded and compared. All the EUS and imaging results were reviewed by a pancreatic surgeon and/or a pancreatologist. Diffuse main duct dilation was defined as dilation of the MPD throughout the entire pancreas. The following dynamic parameters were calculated: increase of main duct dilation (in millimeter and percentage), increase in size of branch-duct IPMN (in millimeter and percentage), time to main duct involvement (if initially isolated branch duct), speed of branchduct IPMN size increase, and speed of main duct diameter increase. The speed of increase was defined as the differential between the size/diameter at diagnosis and the maximal size/diameter, divided by the time to reach maximal size/diameter.
Statistical Analysis Data were compiled using Microsoft Excel 2011 (Microsoft Corp, Redmond, WA). Descriptive statistics of continuous data included mean, standard error, and range, whereas categorical variables were presented as percentages. Subgroup comparisons on continuous and categorical data were performed with the Student t test and the Fisher exact test, respectively. Statistical significance was considered at a P value of less than 0.05. Independent predictors of malignant progression were determined with univariate and multivariate analyses using a logistic www.annalsofsurgery.com | 681
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regression model. Parameters associated with a P value of less than 0.1 on univariate analysis were candidate for the multivariate model. Only variables that remained statistically significant with a P value of less than 0.05 were included in the final model. To assess the performance characteristics of our model of predictors, we generated receiver operating characteristic curves and calculated the area under the curve. All analyses were performed using IBM SPSS statistics version 21.0 (IBM Corp, Armonk, NY).
RESULTS Population Characteristics Eight hundred sixty-five patients had a diagnosis of IPMN and were treated at Indiana University Medical Center from 1992 to 2012. Among them, 362 (41.8%) underwent primary surgical resection whereas 503 (58.2%) underwent primary surveillance. Of the 503 patients in the surveillance program, 95 (11%) were identified with MPD-involved IPMN (main duct IPMN and mixed-type IPMN). After exclusion of patients with incomplete data for analysis and patients with less than 6-month follow-up and 2 clinic visits, there remained 72 patients with MPD-involved IPMN. Of these, 70 patients (8.1%) had the mixed-type IPMN subtype and were included in this study. Those 70 patients were consisted of 40 men and 30 women (sex ratio = 1.33), with a mean age at initial diagnosis of 68.8 ± 11.2 (range, 33–85) years. Patient selection is summarized in Figure 1.
Primary Surveillance Indications for Nonsurgical Management Surgery was contraindicated in 29 of 70 patients (41.5%) because of 1 or multiple relevant and major comorbidities (American Association of Anesthesiologists score ≥3). Comorbidities included synchronous extrapancreatic malignancies in 4 patients (5.7%), cardiovascular disease in 13 patients (18.6%), respiratory insufficiency
in 5 patients (7.1%), end-stage renal insufficiency in 3 patients (4.3%), cirrhosis in 1 patient (1.4%), and various other comorbidities in the remaining 3 patients (4.3%) (eg, morbid obesity, chronic diseases requiring prolonged use of steroids). Thirty-six patients (51.4%) refused surgery after being appropriately informed of the invasive potential of their disease and the indication for surgical management. Finally, the 5 remaining patients (7.1%) underwent surveillance because of borderline criteria for mixed-type IPMN (MPD dilation; range, 5–6 mm). Of those 5 patients, 3 ultimately underwent surgical resection of their lesion during follow-up. Final pathology of the surgical specimen confirmed mixed-type IPMN in all 3 patients. For the remaining 2 patients, a diagnosis of mixed-type variant was made on cytopathology (aspiration of the MPD fluid had features diagnostic of IPMN on cytology).
Type and Duration of Surveillance Patients with a diagnosis of mixed-type IPMN on study underwent primary surveillance for a median of 4.5 years (mean = 4.7 ± 2.7 years; range, 0.6–10.2 years). Fifty-five patients (78.6%) underwent only surveillance, whereas 15 patients (21.4%) underwent primary surveillance and delayed surgery at a median of 2.4 years (mean 2.7 ± 2.1 years; range, 0.6–9 years) from the onset of primary surveillance. The indication for secondary surgery in 3 patients (4.3%) was a cytopathologic diagnosis of an invasive IPMN. The remaining 12 patients (80%) with secondary operations had noninvasive mixed-type IPMN (9 low-grade dysplasia and 3 moderate-grade dysplasia). Their indications for secondary surgery were symptoms (n = 5) [including weight loss (n = 2), recurrent acute pancreatitis (n = 2), new-onset diabetes (n = 1)], radiologic features (n = 4), increased main duct dilation (n = 1), increased branch-duct size (n = 1), increased uptake on positron emission tomography– computed tomography (n = 2), patient change in preference (n = 2), and molecular changes (n = 1) (specifically, increased clonality of mutations).
Invasive Progression Characteristics of Patients Who Progressed Nine patients (12.9%) progressed to invasive carcinoma during follow-up. Clinical aspects of patients with an invasive progression are summarized in Table 1. According to this table, 1 patient (11.1%) with an invasive progression did not meet either the Sendai criteria5 (symptoms, MPD diameter ≥15 mm, mural nodule, cyst size >3 cm) or the high-risk stigmata of the 2012 ICGs6 (jaundice, solid component, MPD diameter ≥10 mm). Of the 9 patients, 6 (66.7%) did not undergo surgery. Of these 6, 3 patients had stage IV disease involving liver (n = 2) or peritoneum (n = 1). Three patients had locally advanced tumor, specifically encasement of the celiac axis (n = 1), superior mesenteric artery (n = 1), or common hepatic artery (n = 1). Among the remaining 3 patients (33.3%) who underwent surgery, 2 received a diagnosis of locally advanced tumors intraoperatively. These patients did not undergo resection and underwent exploratory laparotomy (n = 1) and palliative double bypass (n = 1). Only 1 patient had pancreatic resection (pancreaticoduodenectomy). Pathology of the surgical specimen revealed T3N1M0 poorly differentiated adenocarcinoma (4.7 cm, with 9/18 positive lymph nodes).
Time to Progression FIGURE 1. Patients’ selection process. BD indicates branch duct; MT, mixed-type. 682 | www.annalsofsurgery.com
Progression of the 9 patients in this study to invasive mixedtype IPMN occurred at a median of 2.7 years (mean = 3.5 ± 2.6 years; range, 1–9 years). Annual cumulative risk of invasive carcinoma in our population of followed mixed-type IPMN is shown in Figure 2. C 2014 Lippincott Williams & Wilkins
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Surveillance of Mixed-Type IPMN
TABLE 1. Characteristics of the 9 Patients with Invasive Progression of Mixed-Type IPMN Age, yr 62 80 64 67 73 77 58 52 85
Sex
Symptoms
Acute Pancreatitis
Jaundice
Maximal MPD Diameter, mm
Maximal BD Size, mm
Mural Nodule
Male Female Male Male Female Male Female Male Female
Yes Yes Yes No Yes No Yes Yes Yes
No No Yes No Yes No Yes No No
No No No No Yes Yes Yes No Yes
10 6 10 5 20 7 8 11 8
120 42 19 25 56 32 10 45 5
No No No No Yes No No Yes No
BD indicates branch duct.
FIGURE 2. Cumulative rate of patients who progressed and who did not progress according to the duration of surveillance after diagnosis of mixed-type IPMN.
There was a stepwise increase in the cumulative incidence of progression with duration of surveillance, resulting in 3- and 5-year invasive progression risks of 7.1% and 10%, respectively.
Uni- and Multivariate Analyses of Patients With Invasive Progression Versus Those Without Univariate Analysis Univariate analysis yielded the following potential predictors for an invasive progression as significant (Table 2): weight loss (P = 0.08), time to main duct involvement (P = 0.07), diffuse main duct dilation (P = 0.01), increase of main duct diameter (P = 0.02), absence of intra-abdominal extrapancreatic cysts (hepatic, renal, ovarian, splendid) (P = 0.009), elevated serum CA19-9 levels (defined as >37 units/mL) (P = 0.009), and elevated serum alkaline phosphatase levels (defined as >125 ng/mL) (P = 0.03). Interestingly, usual predictors of invasiveness (mural nodule, maximum main duct diameter, maximal branch-duct size, main duct diameter >10 mm, and branch-duct size > 30 mm) were not significant on univariate analysis (P = 0.17, P = 0.48, P = 0.98, P = 0.22, and P = 0.47, respectively). Because of its well-established association with invasive potential, jaundice was excluded from univariate and multivariate analyses. Of note, 29 patients (41%) received a diagnosis of 1 or multiple branch-duct IPMNs first with a delayed diagnosis of main duct involvement, which was then confirmed on cytopathology of the C 2014 Lippincott Williams & Wilkins
MPD fluid. In those cases, however, we considered the time when the main duct component was diagnosed as the starting point for all follow-up, invasive progression, and survival durations to avoid any bias.
Multivariate Model In logistic regression, diffuse main duct dilation, elevated serum CA19-9 levels, elevated serum alkaline phosphatase levels, and absence of extrapancreatic cysts were predictors of an invasive progression with odds ratios of 7.4, 10, 6.9, and 12.3, respectively (Table 3).
Performance of Predictors The receiver operating characteristic curve indicated that the combination of these 4 predictors (diffuse main duct dilation, elevated serum CA19-9 levels, elevated serum alkaline phosphatase levels, and absence of extrapancreatic cysts) achieved a sensitivity of 77.8% and a specificity of 98.4% in predicting invasiveness. This resulted in an accuracy of 98% for invasive progression prediction. In the group of patients without progression (n = 61), 16 patients (26.2%) had no predictor, 35 (57.4%) had 1 predictor, 9 (14.7%) had 2 predictors, 1 (1.6%) had 3 predictors, and none had all 4 identified predictors. Conversely, in the invasive progression group, no patient had zero or 1 predictor, 3 (33.3%) had 2 predictors, www.annalsofsurgery.com | 683
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TABLE 2. Univariate Analysis Characteristics Sociodemographic Age, mean ± SD, yr Obesity, n (%) BMI, mean ± SD, kg/m2 History of smoking, n (%) Alcohol abuse, n (%) Personal history of cancer, n (%) Family history of pancreatic cancer, n (%) Clinical, n (%) Symptoms (in general) Abdominal/back pain Nausea/vomiting Weight loss Steatorrhea Diabetes Acute pancreatitis Biological, n (%) Elevated serum CA19-9 Elevated HbA1c Abnormal amylase Abnormal lipase Elevated serum alkaline phosphatase Radiological/endoscopic Mural nodule, n (%) Maximal MPD diameter, mean ± SD, mm MPD diameter >10 mm, n (%) Maximal BD size, mean ± SD, mm BD size >30 mm, n (%) Diffuse dilation MPD, n (%) Multifocal BD-IPMN, n (%) Lymph nodes, n (%) Absence of extrapancreatic cysts, n (%) Dynamic parameters, mean ± SD Increase dilation of MPD diameter, mm Increase dilation of MPD diameter, % Increase size BD, mm Increase size BD, % Time to MPD involvement Speed of MPD diameter increase, mm/yr Speed of BD size increase, mm/yr
No Invasive Progression (n = 61)
Invasive Progression (n = 9)
P
68.9 ± 11.3 17 (27.9) 27.6 ± 5.0 35 (57.4) 16 (26.2) 14 (23.0) 7 (11.5)
68.7 ± 10.9 0 (0) 23.8 ± 2.6 4 (44.4) 2 (22.2) 4 (44.4) 0 (0)
0.96 0.11 0.16 0.5 1 0.22 0.58
48 (78.7) 40 (65.6) 11 (18) 20 (32.8) 13 (21.3) 19 (31.1) 23 (37.7)
7 (77.8) 7 (77.8) 2 (22.2) 6 (66.7) 2 (22.2) 3 (33.3) 3 (33.3)
1 0.71 0.67 0.08∗ 1 1 1
8 (13.1) 17 (27.9) 4 (10) 1 (7.1) 12 (19.7)
5 (55.6) 5 (55.6) 1 (7.7) 3 (8.6) 5 (55.6)
0.009∗ 0.13 1 1 0.03∗
4 (6.6) 8.4 ± 4.7 14 (23) 22.5 ± 14.8 24 (39.3) 13 (21.3) 45 (73.8) 13 (21.3) 24 (39.3)
2 (22.2) 9.5 ± 4.4 4 (44.4) 38.3 ± 33.9 5 (55.6) 6 (66.7) 5 (55.6) 2 (22.2) 8 (88.9)
0.17 0.48 0.22 0.98 0.47 0.01∗ 0.26 1 0.009∗
1.4 ± 2.3 21.6 ± 32.8 6.1 ± 8.4 39.7 ± 60.2 0.72 ± 1.3 1.2 ± 2.6 2.9 ± 4.8
3.1 ± 5 58.5 ± 100 21.6 ± 27.6 263.7 ± 415.2 2 ± 3.1 2.1 ± 3.3 7.9 ± 11.2
0.02∗ 0.02∗ 0.76 0.150 0.07∗ 0.31 0.34
Elevated serum CA19-9 defined by CA19-9 >37 units/mL; elevated HbA1c defined by HbA1c >5.9%; abnormal serum amylase defined by serum amylase level 125 units/L; abnormal serum lipase defined by serum lipase level 51 units/L; elevated serum alkaline phosphatase defined by alkaline phosphatase >125 ng/mL. ∗ P value considered statistically significant in univariate analysis ( 37 units/mL; elevated serum alkaline phosphatase defined by alkaline phosphatase >125 ng/mL. ∗ P value considered statistically significant in univariate analysis (
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